Here is a question from my (Geo) friend and colleague, Kathryn Doig, MLS, PhD: “We all know that some women are prone to clots with both birth control hormones and menopausal hormones, but I want to understand why. I found a good review article with a reference (I have since lost) that showed an increase of FII, FVII, VIIa, CRP, and D-dimers and a decrease in PAI1 and TPA with oral estrogen formulations, but not with transdermal administration. I was never able to find an explanation for the mechanism by which oral estrogens (with first pass through the liver) have these impacts. I am wondering if you know? In a related question, why is the combination of oral estrogen with oral progesterone even more prone to clotting?”
I chatted with Kathy and admitted I know little about the mechanisms that connect estrogen and progesterone with thrombosis, and have begun a lit search, so meanwhile, I’m reaching out to colleagues and Fritsma Factor participants who possess endocrine expertise. Thanks for reading and, hopefully, responding.
Hi George,
Let me begin with a disclaimer in the form of a somewhat tedious introduction. Whenever I hear the word “mechanism” in relation to coagulation, my eyes start to twitch. This comes partly from my background in enzymology and chemistry, where a mechanism, by definition, should explain how something happens—through a clear, step-by-step sequence of events. In medicine, the same principle applies: a mechanism should trace the path from cause to effect in a logical chain. Across all fields of science, a proposed mechanism remains valid only as long as it accounts for the majority of experimental data and observations. Once it begins to fail in explaining evidence—and especially when new exceptions accumulate—it must eventually be replaced with a new framework that reconciles both old and new findings.
Seeking mechanisms in coagulation, however, is especially challenging because of the system’s complexity and its intimate entanglement with the immune system and inflammation—two of the great black boxes of human biology. With this in mind, I hope readers will realize why any claim of a definitive mechanism in this field must be made with caution, given the frequent presence of conflicting evidence gathered by biomarker measurements or risk factor correlations.
Estrogen and progesterone exert their effects primarily through nuclear receptors that regulate gene expression. It is therefore reasonable to expect that they may up-regulate procoagulant proteins (FVII) or down-regulate natural anticoagulants (PS) and fibrinolytic factors (tPA) in hepatocytes. These effects are dose-dependent, with greater impact from oral formulations due to their first-pass metabolism in the liver compared to transdermal delivery. Furthermore, different routes of administration generate distinct metabolites, some of which may have divergent biological activity. Progesterone co-administration likely amplifies estrogen receptor activity, further shifting haemostatic balance toward thrombosis. On top of this, endothelial activation, platelet reactivity, circulating microparticles, plasma phospholipid profiles, and even individual baseline temperature contribute to the variability of thrombotic risk, making any single “mechanism” difficult to define.